Adenosine is an endogenous purine nucleoside that modulates a variety of physiological processes. At present, four adenosine receptor subtypes belonging to the family of G protein-coupled receptors (GPCRs) have been cloned and characterized (A1, A2A, A2B, and A3). Among four adenosine receptors, A2AReceptors (A2ARs) appear to play the most important role in the control of motor behavior and in the modulation of dopamine-mediated responses (Pinna, A.; Wardas, J.; Simola, N.; Morelli, M.; Life Sci. 2005, 77, 3259-3267). These observations support therapeutic use of A2A antagonists for neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease.
PD is a neurodegenerative disorder characterized by the loss of motor coordination manifested as tremor and rigidity of the limbs and trunk (Jenner, P.; Neurology 2003, 61, S32-S38). These symptoms are due to the deterioration and loss of dopaminergic neurons in the pars compacta region of the substantia nigra, which result in a decrease of dopamine in the striatum (Gillespie, et al. Neurology 2003, 61, 293-296.)
The finding revealed that the A2AR is primarily located in the striatum and is co-expressed with the dopamine D2 receptor which supports the role for A2A in motor activity (Shih-Jen, T. Medical hypotheses 2005, 64, 197-200). Results from different studies showed that A2ARs exert an excitatory influence on striatopallidal neurons, which is partially related to their antagonistic effect on dopamine D2 receptor activation (Cieślak, M.; Komoszyńsk, M.; A Wojtczak Purinergic Signalling 2008, 4, 305-312) This functional interaction has suggested new therapeutic approaches for PD, based on the use of selective A2AR antagonists. Therefore, antagonists of the A2A subtype of adenosine receptor have emerged as a leading candidate class of nondopaminergic antiparkinsonian agents (Kashe, H.; Biosci, Biotechnol, Bichem 2001, 65, 1447-1457). The effects of A2A antagonists have also been reported to afford neuroprotection in animal models of PD (Chen et al. Progress in Neurology, 2007, 83, 310-331)

In the past ten years, great efforts have been devoted to identify potent and selective A2A adenosine antagonists. Recently, there has been much progress made in the discovery of small molecules as A2A antagonists and compounds such as KW-60021 has been the subject of clinical evaluation. These xanthine-based compounds have been reported to possess efficacy in models of the Parkinson's disease without inducing hyperactivity or inducing dyskinesias. (Kanda, T.; Jackson, M. J.; Smith, L. A.; Pearce, R. K. B.; Nakamura, J.; Kase, H.;
Kuwana, Y.; Jenner, P. Exp. Neurol. 2000, 162, 321). More recently, the compound has been the subject of clinical evaluation, but failed to meet primary endpoints in two of the three essential trials (http://www.kyowa-kirin.co.jp/english/news/2009/e20090115—01.html). Additional non-xanthine compound such as SCH58261 have been reported and widely studied (Baraldi et al. J. Med. Chem. 2002, 45, 115) However, SCH 58261 suffered from several drawbacks including lower selectivity, poor solubility and pharmacokinetic profile.
In view of the limitation as described above for the use of known A2Aantagonist for the treatment of the central nervous system disorder such as Parkinson disease, there is need to develop novel compounds as A2A antagonist, free from the above said drawbacks.
Thiazoles have emerged as important class of compounds due to their antioxidant, anti-inflammatory, and neuro-protective effects (Hirota, T.; Leno, K.; Sasaki, K.; J. of Heterocyclic Chemistry, 1986, 23, 1685). A series of aryl/heteroaryl urea bearing thiazole moiety have emerged as a potent and selective inhibitors of cyclin dependent kinases for the treatment of Alzheimer's disease and other neurodegenerative disorders (Helal et al, Bioorg. Med. Chem. Lett. 2004, 14, 5521-5525).
Thiazolo[4,5-d]pyrimidine derivatives, which can be considered as thiole-analogues of the natural purine bases such as adenine and guanine, have acquired a growing importance in the field of medicinal chemistry because of their biological potential (Zhi, H.; Chen, L. M.; Zhang, L. L.; Liu, S. J.; Wan D. C. Cheong; Lin, H. Q.; Hu. C. ARKIVOC 2008 (xiii) 266-277). Furthermore, the recently demonstrated adenosine A2A receptor antagonistic activities of certain thiazoles with a urea moiety (Slee, D.; Lanier M.; Vong, B. G.; Chen, Y.; Zhang, X.; Lin. E.; Moorjani; M.; Castro, P.; Laria, J. C.; U.S. Pat. No. 20,080,275,064, 6 Nov. 2008) and thiazolopyrimidines (Sugihara, Y.; Kawakita, Y.; U.S. Pat. No. 20,080,269,238, 30 Oct. 2008) for the development of a suitable approach to the treatment of PD.
In the present invention, novel thiazolo-pyrimidine pharmacophore was constructed with urea and furonamide moiety possessing aliphatic flexible groups, and aromatic planer structures as side chains as a potential A2A receptor antagonist.